Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C0022116 (ischemia)
 91,303 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Adenosine and acetylcholine (ACh) trigger preconditioning by different signaling pathways. The involvement of phosphatidylinositol 3-kinase (PI3-kinase), a protein tyrosine kinase, and Src family tyrosine kinase in preconditioning was evaluated in isolated rabbit hearts. Either wortmannin (PI3-kinase blocker), genistein (tyrosine kinase blocker), lavendustin A (tyrosine kinase blocker), or 4-amino-5-(4-chlorophenyl)-7-(t-butyl)pyrazolol[3,4-d]pyrimidine (PP2; Src family tyrosine kinase blocker) was given for 15 min to bracket a 5-min infusion of either adenosine or ACh (trigger phase). The hearts then underwent 30 min of regional ischemia. Infarct size for ACh alone was 9.3 +/- 3.5% of the risk zone versus 34.3 +/- 4.1% in controls. All four inhibitors blocked ACh-induced protection. When wortmannin or PP2 was infused only during the 30-min ischemic period (mediator phase), ACh-induced protection was not affected (7.4 +/- 2.1% and 9.7 +/- 1.7% infarction, respectively). Adenosine-triggered protection was not blocked by any of the inhibitors. Therefore, PI3-kinase and at least one protein tyrosine kinase, probably Src kinase, are involved in the trigger phase of ACh-induced, but not adenosine-induced, preconditioning. Neither PI3-kinase nor Src kinase is a mediator of the protection of ACh.
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PMID:Acetylcholine but not adenosine triggers preconditioning through PI3-kinase and a tyrosine kinase. 1238 36

This study characterized the contributions of protein tyrosine kinase (PTK) and mitogen-activated protein kinase (MAPK) in nociceptin/orphanin FQ (NOC/oFQ)-induced impairment of hypercapnic pial artery dilation (PAD) after hypoxia/ischemia (H/I) in piglets equipped with a closed cranial window. NOC/oFQ (10(-10) M cerebrospinal fluid H/I concentration) impaired hypercapnic PAD (21 +/- 2% vs. 13 +/- 1%). Coadministration of either of the PTK inhibitors genistein or tyrphostin A23 or the MAPK inhibitors U-0126 or PD-98059 with NOC/oFQ (10(-10) M) partially prevented the inhibition of hypercapnic PAD compared with that observed in their absence (21 +/- 2% vs. 17 +/- 1% for genistein). After exposure to H/I, PAD in response to hypercapnia was impaired, but pretreatment with either genistein, tyrphostin A23, U-0126, or PD-98059 partially protected such impairment (17 +/- 1% vs. 4 +/- 1% vs. 9 +/- 1% for sham control, H/I, and H/I + genistein pretreatment, respectively). These data show that PTK and MAPK activation contribute to NOC/oFQ-induced impairment of hypercapnic PAD. These data suggest that activation of PTK and MAPK is also involved in the mechanism by which NOC/oFQ impairs hypercapnic PAD after H/I.
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PMID:PTK, MAPK, and NOC/oFQ impair hypercapnic cerebrovasodilation after hypoxia/ischemia. 1248 17

This study characterized the contributions of protein tyrosine kinase and mitogen-activated protein kinase in nociceptin/orphanin FQ induced impairment of NMDA dilation after cerebral hypoxia/ischemia in anesthetized newborn pigs equipped with a closed cranial window. Topical nociceptin/orphanin FQ, in a concentration observed after hypoxia/ischemia, impaired NMDA pial artery vasodilation. Co-administration either of the protein tyrosine kinase inhibitor genistein or the mitogen activated protein kinase inhibitor U0126 with nociceptin/orphanin FQ partially prevented the inhibition of NMDA dilation compared to that observed in their absence. After exposure to hypoxia/ischemia, pial artery dilation in response to NMDA was reversed to vasoconstriction but pretreatment with either genistein or U0126 partially protected such impairment. These data show that protein tyrosine kinase and mitogen activated protein kinase activation contribute to nociceptin/orphanin FQ induced impairment of NMDA dilation. These data suggest that protein tyrosine and mitogen activated protein kinase are involved in the mechanism by which nociceptin/orphanin FQ impairs NMDA dilation following hypoxia/ischemia.
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PMID:Newborn pig nociceptin/orphanin FQ activates protein tyrosine kinase and mitogen activated protein kinase to impair NMDA cerebrovasodilation after ischemia. 1259 29

In this study, we investigated the effects of protein tyrosine kinase (PTK) and protein tyrosine phosphatase (PTP) on the tyrosine phosphorylation of N-methyl-D-aspartate receptor subunit 2A (NR2A) and the interactions among NR2A, postsynaptic density protein 95 (PSD-95), Fyn/Src after brain ischemia/reperfusion (I/R). The following results were observed: (1) the increase in tyrosine phosphorylation of NR2A induced by I/R was suppressed by genistein, an inhibitor of PTK, but was further enhanced by sodium orthovanadate, an inhibitor of PTP, which were administered to the SD rats 20 min before ischemia. (2) Importantly, genistein and sodium orthovanadate increased and decreased the interactions involving NR2A, PSD-95, Fyn and Src, respectively. These results demonstrated that PTK and PTP were involved in regulating tyrosine phosphorylation of NR2A through changing the interaction among NR2A, PSD-95, Fyn/Src.
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PMID:Tyrosine kinase and tyrosine phosphatase participate in regulation of interactions of NMDA receptor subunit 2A with Src and Fyn mediated by PSD-95 after transient brain ischemia. 1261 93

Previous studies in piglets have shown that the generation of oxygen free radicals (O(-)(2)) following traumatic brain injury and hypoxia/ischemia contribute to the reversal of N-methyl-D-aspartate (NMDA)-induced pial artery dilation to vasoconstriction. This study determined the contribution of protein tyrosine kinase (PTK) and mitogen-activated protein (MAPK) activation to impairment of NMDA cerebrovasodilation by O(-)(2) in piglets equipped with a closed window. Exposure of the cerebral cortex to a xanthine oxidase O(-)(2) generating system (OX) reversed NMDA (10(-8), 10(-6) M) dilation to vasoconstriction but such impairment was partially prevented by the PTK inhibitor, genistein, the MAPK (ERK isoform) inhibitor, U0126, and the MAPK (p38 isoform) inhibitor, SB203580 (9+/-1 and 15+/-1 vs. -1+/-1 and -1+/-1 vs. 5+/-1 and 9+/-1% for sham control, OX and OX in the presence of genistein, respectively). However, the p38 MAPK inhibitor, SB203580, prevented NMDA dilator impairment significantly less than the ERK MAPK inhibitor, U0126. Similar results were obtained for glutamate. These data show that PTK and MAPK activation by the presence of O(-)(2) contributes to the impairment of NMDA dilation. Furthermore, these data indicate a differential role for ERK and p38 MAPK activation in impairment of NMDA dilation by O(-)(2) in the brain.
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PMID:Differential role of PTK, ERK and p38 MAPK in superoxide impairment of NMDA cerebrovasodilation. 1285 May 76

Recently, the neuroprotective effects of lithium against excitotoxicity mediated by N-methyl-D-aspartate (NMDA) receptors have been demonstrated. Since brain ischemia results in NMDA receptor over-excitation and Src family protein tyrosine kinase-mediated tyrosine phosphorylation of NMDA receptor subunit 2A (NR2A) enhances NMDA receptor activity, we examined the effects of lithium on tyrosine phosphorylation of NR2A and its interactions with Src and Fyn (two members of the Src family of protein tyrosine kinases) mediated by PSD-95 (postsynaptic density protein 95 kDa) after 6 h of reperfusion following 15 min of ischemia (I/R), which was induced by occlusion of the four vessels in Sprague-Dawley rats. After abdominal injection of LiCl (2 mg/kg) for 7 days, the data showed that together with the significant decrease in I/R-induced tyrosine phosphorylation of NR2A, the interactions of NR2A with Src and Fyn mediated by PSD-95 were also decreased significantly. However, lithium pretreatment did not alter the total protein levels of NR2A, Src, Fyn and PSD-95. These results suggest that the inhibition of NR2A tyrosine phosphorylation and its interactions with Src and Fyn mediated by PSD-95 may contribute to the lithium-induced downregulation of NMDA receptor function and provide neuroprotection against excitotoxicity.
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PMID:Lithium reduced N-methyl-D-aspartate receptor subunit 2A tyrosine phosphorylation and its interactions with Src and Fyn mediated by PSD-95 in rat hippocampus following cerebral ischemia. 1293 24

Japanese white rabbits underwent 30 minutes of ischemia and 48 hours of reperfusion. Benidipine (3 or 10 microg/kg, i.v.) was administered 10 minutes before ischemia with and without pretreatment with L-NAME (10 mg/kg, i.v., a NOS inhibitor), chelerythrine (5 mg/kg, i.v., a PKC blocker) or 5-HD (5 mg/kg, i.v. a mitochondrial KATP channel blocker), genistein (5 mg/kg, i.v. a protein tyrosin kinase blocker). SNAP (2.5 mg/kg/min x 70 minutes, i.v., an NO donor) was also administered 10 minutes before ischemia. Benidipine significantly reduced the infarct size in a dose-dependent manner (3 microg/kg: 29.0 +/- 2.7%, n = 8, 10 microg/kg: 23.0 +/- 2.4%, n = 10) compared with the control (41.6 +/- 3.3%, n = 10). This effect was completely blocked by L-NAME (39.9 +/- 3.6%, n = 8) and chelerythrine (35.5 +/- 2.4%, n = 8) but not by 5-HD (23.0 +/- 2.4%, n = 10) or genistein (24.6 +/- 3.1%, n = 10). SNAP also reduced the infarct size (24.6 +/- 3.1%, n = 8). Benidipine significantly increased the expression of eNOS mRNA at 30 minutes after reperfusion and significantly increased the expression of eNOS protein at 3 hours after reperfusion in the ischemic area of the left ventricle. Benidipine and SNAP significantly decreased myocardial interstitial 2,5-DHBA levels, an indicator of hydroxyl radicals, during ischemia and reperfusion. Benidipine increased myocardial interstitial NOx levels, which effect was blocked by chelerythrine, during 0 to 30 minutes and 150 to 180 minutes after reperfusion. Benidipine reduces the infarct size through PKC-dependent production of nitric oxide and decreasing hydroxyl radicals but not through involving protein tyrosine kinase or mitochondrial KATP channels in rabbits.
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PMID:Benidipine reduces myocardial infarct size involving reduction of hydroxyl radicals and production of protein kinase C-dependent nitric oxide in rabbits. 1516 67

Focal adhesion kinase (FAK) is a 125 kDa protein tyrosine kinase (PTK) associated with focal adhesion in many cells, which plays a major role in the integrity of cytoskeletal structure. Reactive oxygen species produced during ischemia and reperfusion injury has been found to be an important mediator of signal transduction process. We found that low dose H2O2 induced increased FAK production in pulmonary microvascular endothelial cells, which could be blocked by cycloheximide (CHX), a protein synthesis inhibitor. Pulmonary endothelial cells were cultured on DMEM medium till 100% confluent. H2O2 was added at 100 uM for 30 min. The cells were collected and lysed, then immuno-blotted with anti-FAK antibody. After 30 min treatment, we found a 30%+/-6% (N=5) increase of FAK in H2O2 treated endothelial cells. This increase could be blocked by pretreatment of cells with CHX at 5 ug/ml for 60 min. In both groups, increased phosphorylation of ERK was observed. Immuno-fluorescence revealed increased staining of FAK in the peri-nuclear region of the H2O2 treated endothelial cells. These findings suggest that H2O2 activated MAP kinase pathway leading to increased FAK production at the protein level. FAK is a 125 kDa PTK associated with focal adhesion in many cells, and it plays a major role in the integrity of cytoskeletal structure. FAK is discretely localized to focal adhesions via its C-terminal focal adhesion-targeting (FAT) sequence. FAK is regulated by integrin-dependent cell adhesion and can control tyrosine phosphorylation of downstream substrates, like paxillin. The reactive oxygen species produced during ischemia and reperfusion injury has been found to be an important mediator of the signal transduction process. Although the signaling pathways leading to hydrogen peroxide induced endothelial monolayer permeability remain ambiguous, cytoskeletal proteins are known to be essential for maintaining endothelial integrity and regulating solute flux through the monolayer. Recent evidence has shown that H2O2 stimulates cytoskeleton reorganization, cell growth/proliferation, and DNA synthesis in various cells. In our previous study, we found a significantly increased amount of FAK in endothelial cells treated with low doses of H2O2. Mitogen-activated protein (MAP) kinases are a group of 30- to 110-kDa serine/threonine kinases. MAPKs belong to the group of kinases that are rapidly activated in response to growth factor stimulation. This family of MAPKs includes ERK, and ERK2. The activated MAPK can translocate to the nucleus where it can regulate transcription factors. Activation of p44 and p42 extracellular signal-regulated protein kinases (ERK1 and ERK2) is an important step in the cascade leading to cell growth and proliferation. In order to determine the mechanism of increased FAK production, we investigated the relationship of FAK production and ERK activation.
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PMID:Reactive oxygen species increased focal adhesion kinase production in pulmonary microvascular endothelial cells. 1563 12

Focal adhesion kinase (FAK) is a non-receptor tyrosine kinase thought to play a major role in transducing extracellular matrix (ECM)-derived survival signals into cells. Thus, modulation of FAK activity may affect the linkage between ECM and signaling cascade to which it is connected and may participate in a variety of pathological settings. In the present study, we investigated the effect of neonatal cerebral hypoxia-ischemia (HI) on levels and tyrosine phosphorylation of focal adhesion kinase and the interaction of this enzyme with Src protein tyrosine kinase and adapter protein p130Cas, involved in FAK-mediated signaling pathway. The total amount of focal adhesion kinase as well as its phosphorylated form declined substantially to about 50% of the control between 24 and 48 h after the insult. Concomitantly a decreased association of FAK with its investigated molecular partners, Src kinase and p130Cas protein has been observed. This early response to brain hypoxia-ischemia was attenuated during prolonged recovery with almost complete return to control values at 7 days. These data are indicative of an involvement of FAK-dependent signaling pathway in the evolution of HI-induced neuronal degeneration.
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PMID:Neonatal cerebral hypoxia-ischemia: involvement of FAK-dependent pathway. 1609 66

Acute inflammatory responses are one of the major underlying mechanisms for tissue damage of multiple diseases, such as ischemia-reperfusion injury, sepsis, and acute lung injury. By use of cellular and molecular approaches and transgenic animals, Src protein tyrosine kinase (PTK) family members have been identified to be essential for the recruitment and activation of monocytes, macrophages, neutrophils, and other immune cells. Src PTKs also play a critical role in the regulation of vascular permeability and inflammatory responses in tissue cells. Importantly, animal studies have demonstrated that small chemical inhibitors for Src PTKs attenuate tissue injury and improve survival from a variety of pathological conditions related to acute inflammatory responses. Further investigation may lead to the clinical application of these inhibitors as drugs for ischemia-reperfusion injury (such as stroke and myocardial infarction), sepsis, acute lung injury, and multiple organ dysfunction syndrome.
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PMID:Src protein tyrosine kinase family and acute inflammatory responses. 1658 27


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